Preclinical Development Of A Romidepsin Nanoparticle Demonstrates Superior Tolerability And Efficacy In Models Of Human T-Cell Lymphoma And Large Granular Lymphocyte Leukemia
Pal, I.; Illendula, A.; Joyner, A.; Manavalan, J. S.; Deddens, T. M.; Sabzevari, A.; Damera, D. P.; Zuberi, S.; Marchi, E.; Fox, T. E.; Dunlap-Brown, M. E.; Jayappa, K. D.; Craig, J. W.; Loughran, T. P.; Feith, D. J.; O'Connor, O. A.
Show abstract
Histone deacetylase (HDAC) inhibitors are a widely recognized and valued treatment option for patients with relapsed or refractory peripheral T cell lymphomas (PTCL). Romidepsin is a relatively selective Class I HDAC inhibitor originally approved for patients with relapsed or refractory (R/R) cutaneous T cell lymphoma (CTCL) and subsequently R/R PTCL. Unfortunately, the FDA approval of romidepsin for R/R PTCL was withdrawn due to a negative Phase 4 post-marketing requirement (PMR), diminishing further the treatment options for patients with PTCL. Herein we describe the development of a first-in-class polymer nanoparticle of romidepsin (Nanoromidepsin) using an innovative amphiphilic di-block copolymer-based nanochemistry platform. Nanoromidepsin exhibited superior pharmacologic disposition, with improved tolerability and safety in murine models of T-cell lymphoma. Nanoromidepsin also exhibited superior anti-tumor efficacy in multiple models including in vitro T cell lymphoma (TCL) cell lines, ex vivo LGL leukemia primary patient samples, and murine TCL xenografts. Nanoromidepsin demonstrated greater accumulation in tumors and a statistically significant improvement in overall survival (OS) compared to romidepsin in murine xenograft models. These findings collectively justify the clinical development of Nanoromidepsin in patients with T-cell malignancies.
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